The overall goal of this Program Project is to develop safe and highly efficacious intervention strategies for prevention of melanoma and non- melanoma skin cancers (NMSC) and to develop basic science and clinical research approaches which will serve as models for the chemoprevention of a wide range of human epithelial cancers. Approximately 60% of squamous cell carcinomas (SCC) arise from pre-existing actinic keratoses (AKs) and/or contiguous skin surfaces. Researchers agree that the probability of successfully altering the natural history of any cancer increases by targeting an earlier, rather than a later, time point in carcinogenesis. Therefore, in this Project we propose to conduct two phase IIb randomized placebo-controlled double-blinded, cancer prevention clinical trials in individuals with preclinical AKs. The chemoprevention agents to be used are those identified in prior phase IIb studies as well as in our current Projects. Recently, in a phase III trial in 2297 participants with greater than or equal to 100 AKs, we found that daily supplementation of 25,000 IU of oral vitamin A for 5 years was effective in preventing SCC [hazard ratio of o.74 (95% C.I.: 0.56 - 0.99, p = 0.04) for a few SCC, comparing subjects receiving vitamin A versus placebo]. In this study , oral vitamin A (retinyl palmitate) at 25,00 IU/day and 50,000 IU/day (doses which proved non-toxic in our previous phase IIa study) will be compared to topical 0.1 tretinoin administered for 6 months. In this study, topical tretinoin will be used as a positive control in comparison to two topical chemoprevention agents identified by the results of a concurrent of Project difluoromethylornithine (DFMO), epigallocatechin gallate (EGCG); 9-cis-retinoic acid; or perillyl alcohol. We propose to demonstrate that specific histopathologic and morphometric abnormalities, genetic alterations, and immunohistochemical surrogate endpoint biomarker (SEB) changes can be modulated safely by chemoprevention agents. During these clinical studies we will determine the predictive accuracy of ultraviolet and polarized photography with respect to identification of abnormal histopathologic and morphometric areas of forearm skin epidermis, and ultimately, examine the histopathologic/morphometric and molecular genetic pathogenesis of skin preneoplasia.